Beginning the PGC3 grant - Welcome — UNC School …€¦ · Beginning the PGC3 grant ... Duncan,...
Transcript of Beginning the PGC3 grant - Welcome — UNC School …€¦ · Beginning the PGC3 grant ... Duncan,...
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BeginningthePGC3grant
PatrickSullivanforthePGCUniversityofNorthCarolina/Karolinska Institutet
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PGC(briefly)
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PGCoverview
• 2007-present• 9disorders• 900+scientistsinPGC,largestconsortiumever• Resultsfreelyavailable• Papers:17main,31secondary/methods,75+useourresults• Manyhighlycitedor“hot”papers
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PGC3grant,6/2016– 4/2021
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PGChistory
Aim PGC1 PGC2 PGC3
NIHfunding 2009-11 2011-16 2016-2021
NIH NIMH NIMH NIMH,NIDA
Co-funding – yes* yes*‡
Dataharmonization yes yes yes
Numberofcases 30K 264K 600K+
Aim:GWAS mega-analyses 5 disorders 9 disorders 9disorders
5disorders:ADHD,AUT,BIP,MDD,SCZ
9disorders:addeatingdisorder,OCD/TS,PTSD,SUDs
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ScienceFoundationIreland&NorwegianResearchCouncil
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Coordinatingcommittee(Sullivan)
ADHD(Faraone)
AN(Bulik,Breen)
AUT(Daly)
SUDs(Agrawal)
BIP(Kelsoe,Sklar)
MDD(Sullivan)
OCD/TS(Mathews)
PTSD(Koenen)
SCZ(O’Donovan)
Cross-Disorder(Smoller)
CNV(Sebat)
Statisticalanalysis(Daly)
NIMHGeetha SenthilThomasLehnerAnji Addington
900+investigators
“States’rightsmodel”
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“Growingpains”fixesIn2009,noonethoughtthePGCwouldbearoundin2020…
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Updatedwebpage
Thanks1e6to:KristaLatta,LeaDavis,GeromeBreen,CindyBulik,MichaelGill
Greatsectionsallaround
Inparticular,theextensiveFAQ&newbiesections
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DataAccessCommittee
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PGCtalks
Shifttodisseminationofmethods
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Ricopili training
Ricopili isthePGCgwas pipeline,https://github.com/Nealelab/ricopiliTherehavebeen2trainingsessionsinLondon(June2015&2016)Trained24&45analysts.https://sites.google.com/a/broadinstitute.org/pgc-summer-school-2016
Hopetorepeatin2017
ThankstoCathryn Lewis&GeromeBreen(IOPPNorganizers)StanleyCenterformajorfunding
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Communications
UNClistservs formostgroups
MultipleGoogleGroups
Keygooglegroupisthisone(N=968)https://groups.google.com/forum/?hl=en-GB#!forum/pgc-full-consortium
Pointperson=KristaLattŀ (UNC)
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Bioinformatics
BuildingbioinformaticstoolsonLISAtounderstandoutput• Basicannotations(genes,GWAScatalog,OMIM,psychCNVs,ID/ASD)• Makinga”genematrix”(usingR,extensible,modifiable)• Geneticcorrelations&lookupvsallPGCresults• MakeinputdataforLD-Hub• MAGMApathwayanalysis;TWAS;causalSNPidentification;partitionedLDSC;etc
DoingpilotprojectwithpsychENCODE toaddfunctionalgenomicdata
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PGC3grant
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andBrisbaneAustralia ORCIDlistsADHD,AN,BIPMDDOCD/TSSUD
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Structure
Site Site lead Note 1 2 3 4 5 6
Cardiff O’Donovan,Mick Largest site ✓
Dublin Gill,Michael Big peds ✓
Mass GenHosp Daly,Mark gma/brainstorm ✓✓ ✓
Mt Sinai Sklar, Pamela Targetedseq ✓
UCSD Sebat,Jonathan CNV ✓
UNC Sullivan,Patrick Coordination ✓
Wash UStLouis Agrawal,Arpana SUDs - NIDA ✓
Overall,65%ofbudgetà 9analysts+5datawranglers+coreadminstaff
ThePGCishiring!
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“Findingactionablevariation”
Goalistodeliveractionablefindings,genomicresultsthata) revealthefundamentalbiology,b) informclinicalpractice,andc) delivernewtherapeutictargets
ThisisthecentralideaofthePGC:toconvertgeneticriskfactorsintobiologically,clinically,andtherapeuticallymeaningfulinsights.
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Aim1(corebusiness)
SNPs(a)EnlargeGWASmega-analysestoincreaseunderstandingofdisordersforwhichmajorprogresshasbeenmadeandtoacceleratenewdiscoveries(b)Systematiccross-disorderanalyses(c)Pathwayanalyses.Includeacademicandindustryexpertsinpsychopharmacologytomaximizetherapeuticimplications– paperinpressinNatureNeuroscience
Goal– 100Kcasesforeachdisorder
Common
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Inpreparation(datainPGCorsoon)
Disorder Newloci
SCZ- CLOZUK 50
BIP 12
MDD 9
ADHD- iPSYCH 9
AUT- iPSYCH 5
AN 1
SUDs 1
FingerscrossedforOCD/TS&PTSD
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Ncase withGWAS.pgc1:initialPGCpapers.pgc2:currentNcases .pgc3:conservativeNcase estimatesforQ1/2019
PGC3samplesizes
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What’stheendpoint?
Ncases
Associations
DeadzoneInflection
Linear
True#associations
“Goodenough”• Tagmostgenesonce• Tagmostgenesinkeypathways
Diminishingreturns
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Aim2
Geneticriskscores(GRS)(a) Development:usingexistingdatafromlargelongitudinalcohorts,
evaluatethepleomorphiceffectsofGRSoverdevelopmentaltime(b) Extremes:analyzephenotypedatafromcaseswithveryhighorvery
lowGRStounderstandtheclinicalimpactofgeneticburden(c) Cross-disorder:developageneralGRSforpsychopathologyto
evaluateriskandresilienceacrossPGCdisorders(includesRDoC)
Common
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Aim2– needtoformworkinggroup
Intentionistoformaworkinggroupofstudieswith:• Longitudinalcohortstudies• 2+measurementpoints• Multiplepsychiatricphenotypes(disorderand/orsymptomscales• HaveGWASnow&sharablewithPGC
EmailKristapleaseifyouwanttohearmore
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Aim3BrainstormEstimategeneticcorrelationsamongallPGCdisordersandallCNS-relevantdiseases/quantitativetraitstodevelopacomprehensiveviewofgeneticinfluencesacrossabroadsetofbrainphenotypes.
Common
http://biorxiv.org/content/early/2016/04/16/048991
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Aim4
CNVAnalyzerareCNVsinninepsychiatricdisordersviahigh-qualitymega-analyses,andperformcross-disorderanalysestorevealpleiotropicgeneticeffects.
WeneedtogetintensityfilesuploadedtoLISAThisisbeingcoordinatedbyCNVgroup(JSebat)&workinggroups
Rare
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Aim5
SequencingCharacterizethefullspectrumofgeneticvariation(especiallyrarevariantsofstrongeffect)inregionsimplicatedbyPGCGWAS.Inexpensivelysequencecodingandregulatoryregionsof~200candidategenesin20,000independentsubjects.
Rare
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Aim6
Pedigreesequencing(co-fundedbyScienceFoundationIreland)ThelargenetworkofPGCclinicianshaveidentifiedrare,denselyaffectedpedigrees.Usingwholegenomesequencing(30xcoverage),wewillsystematicallyevaluate~100suchpedigreestoenablesearchesforrarevariantsofstrongeffect.
Rare
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“PGC3:findingactionablevariation”
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Actionable
Goalistodeliveractionablefindings,genomicresultsthata) revealthefundamentalbiology,b) informclinicalpractice,andc) delivernewtherapeutictargets
ThisisthecentralideaofthePGC:toconvertgeneticriskfactorsintobiologically,clinically,andtherapeuticallymeaningfulinsights.
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What’sthelogic?
Geneticfindings
Biology
Pathways/“readouts”
Rationaldrugdiscovery/clinicaluse
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Actionable– rarevariantaims
Aim biol /clin /ther Comment
Rare– 6 – largepedigrees ✓ ✓ Abigswingfor thefence– even1wouldbenotable
Rare– 5 – targetedsequencing ✓ ✓ Canany genesgetovertheexomesigthreshold?
Rare– 4 – CNVs ✓ ✓ ✓ Especially singlegeneCNVs(e.g., NRXN1 &C4 CNP)
Common– 3 – brainstorm
Common– 2 – GRSoverdev
Common– 1 – corebusiness,gwas
Easytoconnectageneticfindingtoaspecificgenewithhypothesisofmechanism
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Actionable– commonvariantaims
Aim biol /clin /ther Comment
Rare– 6 – largepedigrees ✓ ✓ Abigswingfor thefence– even1wouldbenotable
Rare– 5 – targetedsequencing ✓ ✓ Canany exonsgetovertheRVthreshold?
Rare– 4 – CNVs ✓ ✓ ✓ Especially singlegeneCNVs(e.g., NRXN1 &C4 CNP)
Common– 3 – brainstorm ✓ Nosology
Common– 2 – GRSoverdev ✓ Etiology,GxE,gen epi
Common– 1 – corebusiness,gwas ✓ ✓ ✓ Bread-and-butter ofthePGC
Connectionoffindingstogenesrequiresmultipleassumptions
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Howtoconnectcommonvariantstogenes?
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exactly
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HowcanIgetinvolvedwiththePGC?
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Thisisdo-able
MuchofPGCleadershipis55+.Turnoverisgoodforanorganization.ThepeoplewhoareinleadershiprolesinPGCsteppedup:• Volunteered,followedthrough,didtaskswell• Tookonsmallroles,didthemwell,gotmoretodo• Volunteeredtowritepartsofpapers• Wereconsistentlyoncalls PGCFAQ
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N=418 who’ve done ORCID: Abdellaoui, Adkins, Adolfsson, Agartz, Agrawal, Air, Akil, Alda, Alliey-Rodriguez, Andlauer, Andreassen, Anjorin,Arnold, Arranz, Aschauer, Bacanu, Baker, Banaschewski, Barchas, Barta, Bass, Bau, Bauer, Baune, Beekman, Bergen, Berger, Bethell, Bienvenu,Biernacka, Bierut, Bigdeli, Blackwood, Boden, Boehnke, Boks, Boomsma, Boraska Perica, Børglum, Breen, Brown, Bulik, Bunney, Burmeister,Buttenschøn, Byrne, Cappi, Carracedo, Casas Bruguã, Casas Brugué, Castelao, Cath, Cervantes, Chen, Chou, Cichon, Clarke, Collier, Cook,Copeland, Corley, Cormand, Costello, Courtet, Couvy-Duchesne, Craddock, Crowley, Cruceanu, Cullen, Culverhouse, Curtis, Czerski, Dale,Dalsgaard, Dalvie, Dannlowski, Davis, De Geus, Degenhardt, Del Favero, Delorme, Dempfle, Denys, Depienne, Derks, Derringer, Di Florio, Direk,Djurovic, Dmitrzak-Weglarz, Domenici, Doyle, Duncan, Dunn, Eapen, Edenberg, Ehrlich, Elvsåshagen, Esko, Fan, Farrer, Favaro, Fernandez,Fernandez-Aranda, Figee, Fischer, Flickinger, Forstner, Forty, Frank, Fraser, Freimer, Frye, Fullerton, Gaddis, Gelernter, Geller, Gershon, Giegling,Gilbert, Gill, Goes, Gonidakis, Gordon, Gordon-Smith, Grabe, Grados, Green, Greenberg, Grevet, Grice, Grigoroiu-Serbanescu, Grove, Grünblatt,Guan, Guijarro, Guillaume, Guzman-Parra, Haavik, Hack, Hakonarson, Hamilton, Hammerschlag, Hamshere, Hancock, Hanna, Hansen,Hartmann, Hartz, Hatzikotoulas, Hauser, Hautzinger, Hayward, Heath, Heiman, Henders, Herms, Herpertz-Dahlmann, Hervas, Hewitt, Hickie,Hinney, Hoekstra, Hoffmann, Hofman, Hohmann, Holmans, Homuth, Hopfer, Horn, Horwood, Hottenga, Hultman, Hutz, Ibanez, Ising, Jankovic,Jansen, Jimenez-Murcia, Johansson, Johnson, Jones, Juréus, Kandaswamy, Kaprio, Karlsson, Kendler, Kennedy, Kent, Kiefer, King, Kirov, Kittel-Schneider, Kloiber, Klump, Knott, Knowles, Knudsen, Koen, Kogevinas, Konte, Kral, Krauter, Krogh, Kuntsi, Kupka, Kutalik, Landén, Lang, Langley,Lawrence, Leber, Lesch, Levinson, Levy, Lewis, Li, Lichtenstein, Lissowska, Liu, Loo, Lucae, Lynskey, Maaser, Macintyre, Madden, Maes,Magnusson, Maher, Malt, Martin, Mathews, Mattheisen, Mayoral-Cleries, Mcelroy, Mcgough, Mcgrath, Mcguffin, Mcintosh, Mckay, Mclaughlin,Mcqueen, Mcquillin, Medland, Mehta, Melle, Meng, Metspalu, Micali, Middeldorp, Mihailov, Milaneschi, Milani, Mitchell, Moessner,Monteleone, Montgomery, Morken, Mors, Mota, Mühleisen, Müller-Myhsok, Müller-Vahl, Munn-Chernoff, Myers, Nagy, Nauck, Nelson, Nestadt,Nicolini, Nigg, Nöthen, Nurmi, Nurnberger, Nyholt, O'donovan, Oedegaard, Olde Loohuis, Onnink, Ophoff, Ori, Oruc, Owen, Paciga, Pálmason,Papeå¾Ovã¡, Paschou, Pauls, Pearson, Pedersen, Penninx, Pergadia, Perlis, Perry, Peterson, Pettersson, Peyrot, Pfennig, Piras, Polderman,Porteous, Posthuma, Potash, Preisig, Quiroz, Ramos-Quiroga, Rasmussen, Regeer, Reichborn-Kjennerud, Reif, Reinbold, Rhee, Ribases, Rice,Richter, Ridinger, Rietschel, Riley, Ripke, Rivas, Rivera, Rizzo, Rommelse, Rothenberger, Rouleau, Rujescu, Sã Nchez-Mora, Saccone, Saeed Mirza,Samuels, Sànchez-Mora, Sandor, Scherag, Scherbaum, Schimmelmann, Schlögelhofer, Schoevers, Schofield, Schulze, Scott, Shi, Sinnamon, Sinzig,Slof-Op 'T Landt, Smalley, Smit, Smoller, Sonuga-Barke, Soyka, Spalletta, Spijker, Stallings, Steffens, Stein, Stordal, Strauss, Streit, Strohmaier,Stuhrmann, Sullivan, Szatkiewicz, Tansey, Tarnok, Tarter, Teumer, Thapar, Thompson, Thornton, Tiemeier, Tischfield, Todorov, Treutlein, Turecki,Uher, Uhlmann, Uitterlinden, Umbricht, Vaaler, Van Den Heuvel, Van Der Auwera, Van Furth, Van Grootheest, Van Hemert, Vanyukov, Viktorin,Vincent, Völzke, Vulink, Walitza, Wall, Walters, Wang, Wang, Watson, Webb, Weissman, Wellmann, Werge, Willemsen, Wilmot, Winslow, Witt,Wodarz, Worbe, Wray, Xi, Xu, Yanovski, Yao, Yilmaz, Yu, Zai, Zayats, Zeggini, Zerwas, Zill
THANKS
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